Mutation of Ubiquilin 2 (Ubqln2) is linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A prominent feature of Ubqln2-associated diseases is protein aggregation which has been reproduced in our Ubqln2 transgenic and knockin rats. Our preliminary studies show that overexpression of both mutant and wildtype Ubqln2 causes neuron death in transgenic rats, suggesting that excess in normal Ubqln2 is toxic to neurons. Ubqln2 expression must be tightly regulated. To dissect the mechanisms by which pathogenic Ubqln2 causes neurodegeneration, we have created Ubqln2 knockin rats in which a pathogenic mutation is introduced to the Ubqln2. Our Ubqln2 knockin rats differ from the wildtype littermates only in a single nucleotide examined. Therefore, any phenotypes detected in the knockin rats must result from the pathogenic mutation introduced. Using the unprecedented rat models, we will determine how mutant Ubqln2 impacts cellular functions to cause neurodegeneration. We will also examine how Ubqln2 is tightly regulated to maintain its normal levels and thus to avoid its excess in production. By these assays, we will attempt to unravel a mechanism underlying Ubqln2-associated neurodegeneration in the disease.